Viruses belonging to the Flaviviridae family include the hepatitis C virus (HCV). The Flavivirus genus includes more than 68 members separated into groups on the basis of serological relatedness. Clinical symptoms vary and include fever, encephalitis and hemorrhagic fever. Flaviviruses of global concern that are associated with human disease include the dengue hemorrhagic fever viruses (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus.
Examples of antiviral agents that have been identified as active against the flavivirus or pestiviruses include:    (1) Interferon and ribavirin;    (2) Substrate-based NS3 protease inhibitors (WO 98/22496);    (3) Non-substrate-based inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al., Biochemical and Biophysical Research Communications, 238:643-647 (1997); Sudo K., et al. Antiviral Chemistry and Chemotherapy, 9:186 (1998)), including RD3-4082 and RD3-4078, the former substituted on the amide with a 14 carbon chain and the latter processing a para-phenoxyphenyl group;    (4) Thiazolidine derivatives, which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al., Antiviral Research, 32: 9-18 (1996)), especially compound RD-1-6250, possessing a fused cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193;    (5) Thiazolidines and benzanilides, identified in Kakiuchi N. et al. J. FEBS Letters 421, 217-220; and Takeshita N. et al. Analytical Biochemistry, 247: 242-246 (1997);    (6) A phenanthrenequinone, which possesses activity against protease in a SDS-PAGE and autoradiography assay and is isolated from the fermentation culture broth of Streptomyces sp., Sch 68631 (Chu M. et al., Tetrahedron Letters, 37: 7229-7232 (1996)), and Sch 351633, isolated from the fungus Penicillium griscofuluum, which demonstrates activity in a scintillation proximity assay;    (7) Selective NS3 inhibitors based on the macromolecule elgin c, isolated from leech (Qasim M. A. et al., Biochemistry, 36: 1598-1607 (1997));    (8) Helicase inhibitors (U.S. Pat. No. 5,633,358);    (9) Polymerase inhibitors, such as nucleotide analogues, gliotoxin (Ferrari E. et al. Journal of Virology, 73:1649-1654 (1999)), and the natural product cerulenin (Lohmann V. et al., Virology, 249: 108-118 (1998));    (10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5′ non-coding region (NCR) of the virus, or nucleotides 326-348 comprising the 3′ end of the NCR and nucleotides 371-388 located in the core coding region of the HCV RNA;    (11) Inhibitors of IRES-dependent translation;    (12) Nuclease-resistant ribozymes; and    (13) Miscellaneous compounds including 1-amino-alkyloyclohexanes (U.S. Pat. No. 6,034,134 to Gold et al.), alkyl lipids (U.S. Pat. No. 5,922,757 to Chojkier et al.), vitamin E and other antioxidants (U.S. Pat. No. 5,922,757 to Chojkier et al.), squalene, amantadine, bile acids (U.S. Pat. No. 5,846,964 to Ozeki et al.), N-(phosphonoacetyl)-L-aspartic acid, (U.S. Pat. No. 5,830,905 to Diana et al.), benzenedicarboxamides (U.S. Pat. No. 5,633,388 to Diana et al.), polyadenylic acid derivatives (U.S. Pat. No. 5,496,546 to Wang et al.), 2′,3′ dideoxyinosine (U.S. Pat. No. 5,026,687 to Yarchoan et al.), and benzimidazoles (U.S. Pat. No. 5,891,874 to Colacino et al.).
Although there are several treatments available for flaviviral infections, some flaviviral infections fail to respond adequately to currently available treatments. Hence, there is a need to provide additional, effective methods for treating and/or preventing such an infection comprising administration of various analogues of Ara-C.
Ara-C
an arabinofuranosylcytosine nucleoside analogue, and prodrug analogues of Ara-C, including fosteabine (1-β-D-arabinofuranosylcytosine-5′-stearylphosphate; YNK01), have been used effectively to treat acute myelogenous leukemia and lymphocytic leukemias (Gahrton et al., Adv. Cancer Res. 40:255-329 (1983); Keating et al., JAMA 248:2481-2486 (1982); Plunkett et al., Semin. Oncol. 20:50-63 (1993); Maloisel, et al., Leukemia 16(4): 573-80 (2002); Kuhr et al., Leuk. Res. 24(7): 583-587 (2000); Inaba et al., Gan To Kagaku Ryoho. 21(4): 535-538 (1994)).
Moreover, Ara-C homologues, including N4-(dialkylamino)methylene derivatives of 2′-dC have been shown in the past to be effective in the treatment of infections from retroviruses, including HIV (see e.g., Kerr et al., J. Med. Chem. 35:1996-2001 (1992); Kerr et al., J. Pharm Sci. 83(4): 582-586 and U.S. Pat. No. 5,051,498 and 5,886,162).
This invention addresses the need to identify additional, effective methods for treating or preventing Flaviviridae infections by providing methods using ara-C analogue compounds for the effective treatment or prevention of Flaviviridae virus (e.g., hepatitis C virus) infections.